Graduated estrogen contraceptive

ABSTRACT

A multiphasic estrogenic/progestogenic contraceptive regimen that provides for the reduction or elimination of estrogen in the initial phase is disclosed. Also described is a contraceptive kit that may be used to practice the method of the invention.

This application claims the benefit of U.S. Provisional PatentApplication No. 60/520,182, filed Nov. 14, 2003.

BACKGROUND OF THE INVENTION

1. Field of the Invention

This invention is directed to a method of contraception that providesfor the reduction or elimination of estrogen in the initial phase of amultiphasic estrogenic/progestogenic contraceptive regimen withoutcompromising contraceptive efficacy or cycle control. The invention isalso directed to a multiphase contraceptive kit that may be used topractice the method of the invention.

2. Related Background Art

Contraceptive compositions containing both estrogenic and progestogeniccompounds are well known. The progestogenic component of the compositionis primarily responsible for the contraceptive efficacy of thecomposition, while the estrogenic component is employed to reduceundesired side effects, such as breakthrough bleeding or spotting.

The earliest of these estrogenic/progestogenic contraceptivecompositions contained a relatively high level of estrogenic component.A constant goal, however, has been to reduce the estrogenic potency ofsuch compositions without reducing contraceptive efficacy and increasingundesired side effects. As described in U.S. Pat. No. 5,888,543, in anattempt to achieve this goal, numerous regimens have been developed inwhich the progestin/estrogen combination is administered in a monophasicregimen (fixed dose) or as biphasic or triphasic regimens (varied dose).

A particularly advantageous technique for reducing total estrogenicadministration is described in U.S. Pat. No. 4,962,098. This describes atriphasic method of contraception using a progestogen/estrogencombination in which the amount of estrogen is increased stepwise overthe three phases. The first phase is 4-7 days, the second phase is 5-8days and the third phase is 7-12 days. Preferably, the administration ofthe contraceptive compositions for the three phases will be 21 daysfollowed by a 7 day placebo period. For all three phases the progestenis 0.5 to 1.5 mg of norethindrone acetate, while about 10 to 30 mcg ofethinyl estradiol is used in the first phase, about 20 to 40 mcg ofethinyl estradiol is used in the second phase and 30 to 50 mcg ofethinyl estradiol is employed in the third phase.

There is a continuing desire, however, to further reduce the amount ofestrogenic component in an estrogenic/progestogenic composition withcontinued contraceptive efficacy while avoiding undesired side effects.Heretofore it was believed that at least 10 mcg of ethinyl estradiol orits estrogenic equivalent was needed in an estrogenic/progestogeniccomposition to assure contraceptive efficacy. It has now beensurprisingly discovered that the amount of estrogenic component in thefirst phase of a triphasic regimen can be significantly reduced oreliminated without compromising efficacy or cycle control.

SUMMARY OF THE INVENTION

This invention is directed to a multiphasic method of contraception thatprovides for the reduction or elimination of administered ethinylestradiol in the first phase without a reduction in contraceptiveefficacy or an increase in undesired side effects. The method of thisinvention includes administering, in sequential steps, to a female ofchild bearing age the following compositions: (a) composition I forabout 5 to about 9 days; (b) composition II for about 5 to about 9 days;and (c) composition III for about 8 to about 12 days. Compositions I, IIand III all contain a progestogen in an amount equivalent to about 0.3to about 1.5 mg, preferably about 0.5 to about 1.5 mg of norethindroneacetate. Composition I contains an estrogen in an amount equivalent toabout 0 to less than about 10 mcg of ethinyl estradiol and bothcompositions II and III contain an estrogen in an amount equivalent toabout 10 to about 50 mcg of ethinyl estradiol.

Significantly, the sequential administration of compositions I, II andIII is repeated after a period of about 1 to about 4 days has elapsedafter completion of the administration of composition III. Without beingbound by theory, it is believed that this relatively short interimperiod between the sequential administration of theestrogenic/progestogenic components allows for the advantageousreduction or elimination of estrogen from the first phase of theabove-described triphasic regimen without compromising efficacy or cyclecontrol. It is also preferable that the amount of estrogen be increasedby at least an amount equivalent to 5 mcg of ethinyl estradiol betweencomposition II and composition III. In a preferred embodiment of thisinvention, the estrogen is ethinyl estradiol and the progestogen isnorethindrone acetate.

Yet another embodiment of this invention is directed to a multiphasecombination and contraceptive kit comprising a package containing dailydosages of: (a) a Phase I composition containing a progestogen in anamount equivalent to about 0.3 to about 1.5 mg, preferably about 0.5 toabout 1.5 mg of norethindrone acetate and an estrogen in an amountequivalent to about 0 to about 10 mcg of ethinyl estradiol; (b) a PhaseII composition containing a progestogen in an amount equivalent to about0.3 to about 1.5 mg, preferably about 0.5 to about 1.5 mg ofnorethindrone acetate and an estrogen in an amount equivalent to about10 to about 50 mcg of ethinyl estradiol; and (c) a Phase III compositioncontaining a progestogen in an amount equivalent to about 0.3 to about1.5 mg, preferably about 0.5 to about 1.5 mg of norethindrone acetateand an estrogen in an amount equivalent to about 10 to about 50 mcg ofethinyl estradiol; wherein the amount of estrogen in the Phase IIIcomposition is at least an amount equivalent to 5 mcg of ethinylestradiol greater than the amount of estrogen in the Phase IIcomposition. Preferably, the estrogen used in the kit is ethinylestradiol and the progestogen is norethindrone acetate.

DETAILED DESCRIPTION OF THE INVENTION

The method of this invention is practiced by administration of thecompositions in a numeric sequence with the Phase I composition beingused first, the Phase II composition being used second, etc. Ifpackaging and/or other requirements dictate, the method and kitdescribed herein can be employed as part of a larger scheme forcontraception or treatment of gynecological disorders. While thesequence in which Applicant's combinations are administered is importantto their operation, it should be kept in mind that variations in timingand dosage can be tolerated when medical considerations so dictate.

Significantly, the method of this invention provides that the sequentialadministration of compositions I, II and III is repeated after a periodof about 1 to about 4 days has elapsed after the completion of theadministration of composition III. More preferably, the number of daysbetween the completion of the administration of composition III andbeginning the repeated sequential administration of compositions I, IIand III is from about 2 to about 4 days. During this interim period aniron supplement and/or a placebo may be preferably administered on adaily basis, although there is no requirement for the administration ofanything during this interim period, i.e., the period between thecompletion of the prior sequential administration of compositions I-IIIand the start of the next sequential administration of compositionsI-III.

Estrogens which may be used in the present invention include, forexample, ethinyl estradiol, 17β-estradiol, 17β-estradiol-3-acetate,mestranol, conjugated estrogens, USP and estrone or salts thereof. Theamount of estrogen used is described herein as that which is“equivalent” in estrogenic potency to an amount of ethinyl estradiol.The equivalent estrogenic potency of an estrogen to ethinyl estradiolmay be readily determined by one of ordinary skill in the art. It iscontemplated that each Phase could employ one or more differentestrogens that deliver a potency equivalent to the recited amount ofethinyl estradiol. It is also contemplated that the estrogen used in onePhase may be different than that used in another Phase. In a mostpreferred embodiment of this invention, however, the estrogen for eachPhase, if present, is ethinyl estradiol.

Progestogens which may be used in the present invention include, forexample, progesterone and its derivatives such as 17-hydroxyprogesterone esters and 19-nor-17-hydroxy progesterone esters,17-alpha-ethinyl testosterone, 17-alpha-ethinyl-19-nortestosterone(norethindrone) and derivatives thereof, norethindrone acetate,norgestrel, nogestamate, desogestrel andD-17-beta-acetoxy-17-beta-ethyl-17-alpha-ethinyl-gon-4-en-3-one oxime.Other exemplary progestogens include demegestone, drospirenone,dydrogesterone, gestodene, medrogestone, medroxy progesterone and estersthereof. The amount of progestogen used is described herein as thatwhich is “equivalent” in progestogenic potency to an amount ofnorethindrone acetate. The equivalent progestogenic potency of aprogestogen to norethindrone acetate may be readily determined by one ofordinary skill in the art. It is contemplated that each Phase couldemploy one or more different progestogens that deliver a potencyequivalent to the recited amount of norethindrone acetate. It is alsocontemplated that the progestogen used in one Phase may be differentthan that used in another Phase. In a most preferred embodiment of thisinvention, however, the progestogen for each Phase is norethindroneacetate.

Accordingly, in a preferred embodiment of this invention thecompositions employed in accordance with the invention will contain inPhase I about 0.3-1.5 mg, preferably about 0.5-1.5 mg norethindroneacetate and about 0 to less than about 10 mcg ethinyl estradiol,preferably about 0 to about 5 mcg ethinyl estradiol, in Phase II about0.3-1.5 mg, preferably about 0.5-1.5 mg norethindrone acetate and about10-50 mcg ethinyl estradiol, preferably about 20-40 mcg ethinylestradiol, and in Phase III about 0.3-1.5 mg, preferably about 0.5-1.5mg norethindrone acetate and about 10-50 mcg ethinyl estradiol,preferably about 25-50 mcg ethinyl estradiol, wherein the amount ofethinyl estradiol is increased by at least 5 mcg from Phase II to PhaseIII

A significant aspect of the method and kit of this invention is that thePhase I composition has a significantly lower concentration of estrogenequivalent to ethinyl estradiol than previously considered possible,while maintaining contraceptive efficacy and avoiding or minimizingunwanted side effects such as break through bleeding. In oneparticularly preferred embodiment the amount of estrogen equivalent toethinyl estradiol in the Phase I composition is about 5 mcg. In anotherparticularly preferred embodiment the Phase I composition issubstantially free of estrogen, and most preferably is substantiallyfree of ethinyl estradiol. As used herein “substantially free” meansthat estrogen is not detectable or only pharmacologically insignificantminor levels are present.

An optional Phase IV composition, which contains an iron supplement,e.g., ferrous fumarate, and/or one or more placebos, can be used inconjunction with the other three.

The particularly preferred compositions employed in accordance with theinvention in Phases I through IV will more preferably have theadministration times and drug contents set forth in the following tableswhen a four-phase system is used. Each table sets forth relevant valuesfor one of Applicant's preferred embodiments, or configurations, foradministration of the system to females. TABLE 1 mg Norethindrone PhaseDays acetate mcg EE mg Fumarate I 7 1.0  5 0 II 7 1.0 30 0 III 10 1.0 350 IV 4 — — 75

TABLE 2 mg Norethindrone Phase Days acetate mcg EE mg Fumarate I 7 1.0 0 0 II 7 1.0 30 0 III 10 1.0 35 0 IV 4 — — 75

The norethindrone acetate (NA) and ethinyl estradiol (EE) are well knownand readily available. Clearly, the amount of NA and EE may be varied inaccordance with the disclosure of this invention. For example, theamount of NA set forth in Tables 1 and 2 could readily be adjusted from1 mg to 0.5 mg or 0.4 mg.

The designation “mcg” refers to micrograms and “mg” to milligrams.

It should be noted that these tables are presented for illustrativepurposes only. The substitution of functionally equivalent amounts andkinds of reagent(s) in these schemes is contemplated. For example, theuse of sugar or other placebo in place of all or part of the ferrousfumarate is envisioned.

The compositions used in this invention are administered using asuitable daily dosage form. Tablets, pills, capsules and caplets areexemplary dosage forms.

In addition, the use of other conventional additives, e.g., fillers,colorants, polymeric binders, and the like is also contemplated. Ingeneral any pharmaceutically-acceptable additive which does notinterfere with the function of the active components can be used in oneor more of the compositions.

Suitable carriers with which the compositions can be administeredinclude lactose, starch, cellulose derivatives and the like used insuitable amounts. Lactose is a preferred carrier. Mixtures of carriers,e.g. lactose, microcrystalline cellulose and starch, are operable.

While the norethindrone acetate is preferred, as previously noted it maybe replaced by a different progestogen. Similarly, while the ethinylestradiol component is preferred it may be completely or partiallyreplaced with one or more conventional estrogenic substances, e.g.,mestranol.

While the invention is discussed as potentially one employing fourphases, it clearly may employ only three. Phase IV is not essential tothe operation of the other three distinct phases. Thus a method or kitwhich does not contain the Phase IV component is operable and, in fact,will be preferred when suitable factors, e.g., economy, dictate thenon-use of the Phase IV component. As previously noted, whether a PhaseIV component is used or not, it is preferably that the period betweenthe completion of the Phase III composition and the start of the Phase Icomposition in the subsequent sequence not exceed about 4 days.

The terms “method” and “kit” are used herein to encompass any drugdelivery systems via the use of which the 3- or 4-phase scheme outlinedabove can be effectively administered to human females. Combinations ofvarious dosage forms are operable.

A unique dosage pattern, i.e., a unique sequence of administration of anovel estrogen/progestogen combination has been discovered whichminimizes the administration of estrogen in the first phase of amultiphase regimen, while also minimizing certain side effects, notablybreakthrough bleeding, commonly associated with conventional low dosagepills.

Reasonable variations, such as those which would occur to a skilledartisan, can be made herein without departing from the scope of theinvention.

1. A method of contraception comprising the steps of sequentiallyadministering to a female of child bearing age: (a) a composition Icontaining a progestogen in an amount equivalent to about 0.3 to about1.5 mg norethindrone acetate and an estrogen in an amount equivalent toabout 0 to less than about 10 mcg of ethinyl estradiol for about 5 toabout 9 days; (b) a composition II containing a progestogen in an amountequivalent to about 0.3 to about 1.5 mg of norethindrone acetate and anestrogen in an amount equivalent to about 10 to about 50 mcg of ethinylestradiol for about 5 to about 9 days; and (c) a composition IIIcontaining a progestogen in an amount equivalent to about 0.3 to about1.5 mg of norethindrone acetate and an estrogen in an amount equivalentto about 10 to about 50 mcg of ethinyl estradiol for about 8 to about 12days, wherein the sequential administration of compositions I, II and Inis repeated after a period of about 1 to about 4 days has elapsed afterthe completion of the administration of composition III.
 2. The methodaccording to claim 1, wherein composition I contains an estrogen in anamount equivalent to about 0 to about 5 mcg of ethinyl estradiol.
 3. Themethod according to claim 1, further comprising the step ofadministering on a daily basis a composition IV containing ferrousfumarate between the completion of the administration of composition IIIand beginning the repeated sequential administration of compositions I,II and III.
 4. The method according to claim 1, further comprising thestep of administering on a daily basis a composition IV which is aplacebo between the completion of the administration of composition IIIand beginning the repeated sequential administration of compositions I,II and III.
 5. The method according to claim 1, wherein composition I issubstantially free of estrogen.
 6. The method according to claim 1,wherein the amount of estrogen in Composition III is greater than theamount of estrogen in composition II by at least an amount equivalent to5 mcg of ethinyl estradiol.
 7. The method according to claim 1, whereinthe progestogen in each composition is norethindrone acetate.
 8. Themethod according to claim 1, wherein the estrogen in each composition isethinyl estradiol.
 9. The method according to claim 8, whereincomposition I contains an amount of ethinyl estradiol from about 0.5 toabout 5 mcg.
 10. The method according to claim 9, wherein composition Icontains about 5 mcg of ethinyl estradiol.
 11. The method according toclaim 8, wherein composition I is substantially free of ethinylestradiol.
 12. The method according to claim 8, wherein the amount ofethinyl estradiol in composition III is at least 5 mcg greater than theamount of ethinyl estradiol in composition II.
 13. The method accordingto claim 8, wherein composition I contains about 0 to about 5 mcg ofethinyl estradiol and the amount of ethinyl estradiol in composition IIIis at least 5 mcg greater than the amount of ethinyl estradiol incomposition II.
 14. The method according to claim 13, further comprisingadministering on a daily basis a composition IV which contains ferrousfumarate or is a placebo for about 1 to 4 days.
 15. The method accordingto claim 14, wherein the sequential administration of compositions I,II, III and IV is repeated upon completion of the administration ofcomposition IV.
 16. The method according to claim 14, wherein the dailyadministration of compositions I, II, III and IV is for a 19 to 34 dayperiod.
 17. The method according to claim 16, wherein the dailyadministration of compositions I, II, III and IV is for a 28 day period.18. The method according to anyone of claims 1 to 6, wherein each ofcompositions I, II and III contain a progestogen in an amount equivalentto about 0.5 to about 1.5 mg of norethindrone acetate.
 19. The methodaccording to anyone of claims 7 to 17, wherein each of compositions I,II and III contain norethindrone acetate in an amount from about 0.5 toabout 1.5 mg.
 20. The method according to claim 17, wherein compositionI contains about 1.0 mg of norethindrone acetate and is administered forabout 7 days, composition II contains about 1.0 mg of norethindroneacetate and is administered for about 7 days, composition III containsabout 1.0 mg of norethindrone acetate and is administered for about 10days, and composition IV contains about 75 mg of ferrous fumarate and isadministered for about 4 days.
 21. The method according to claim 20,wherein composition I contains about 5 mcg of ethinyl estradiol,composition II contains about 30 mcg of ethinyl estradiol andcomposition III contains about 35 mcg of ethinyl estradiol.
 22. Themethod according to claim 21, wherein composition I is substantiallyfree of ethinyl estradiol, composition II contains about 30 mcg ofethinyl estradiol and composition III contains about 35 mcg of ethinylestradiol.
 23. A method of contraception comprising the steps ofsequentially administering to a female of child bearing age: (a) acomposition I containing about 0.3 to about 1.5 mg norethindrone acetateand about 0 to about 5 mcg of ethinyl estradiol for about 5 to about 9days; (b) a composition II containing about 0.3 to about 1.5 mgnorethindrone acetate and about 20-40 mcg ethinyl estradiol for about 5to about 9 days; (c) a composition III containing about 0.3 to about 1.5mg norethindrone acetate and about 25-50 mcg ethinyl estradiol for about8 to about 12 days; and (d) optionally a composition IV that containsferrous fumurate or is a placebo for about 1 to about 4 days, whereinthe sequential administration of compositions I, II and III is repeatedand the number of days between completion of the administration ofcomposition III and beginning the repeated sequential administration ofcompositions I, II and III is from about 1 to about 4 days.
 24. Themethod according to claim 23, wherein composition III contains at least5 mcg of ethinyl estradiol more than composition II.
 25. The methodaccording to claim 24, wherein composition IV is administered on a dailybasis between the completion of the administration of composition IIIand beginning the repeated sequential administration of compositions I,II and III.
 26. The method according to anyone of claims 23 to 25,wherein each of compositions I, II and III contain about 0.5 to about1.5 mg of norethindrone acetate.
 27. A multiphase combination andcontraceptive kit comprising a package containing daily dosages of: (a)a Phase I composition containing a progestogen in an amount equivalentto about 0.3 to about 1.5 mg of norethindrone acetate and an estrogen inan amount equivalent to about 0 to about 5 mcg of ethinyl estradiol; (b)a Phase II composition containing a progestogen in an amount equivalentto about 0.3 to about 1.5 mg of norethindrone acetate and an estrogen inan amount equivalent to about 10 to about 50 mcg of ethinyl estradiol;and (c) a Phase III composition containing a progestogen in an amountequivalent to about 0.3 to about 1.5 mg of norethindrone acetate and anestrogen in an amount equivalent to about 10 to about 50 mcg of ethinylestradiol, wherein the amount of estrogen in the Phase III compositionis greater than the amount of estrogen in the Phase II composition by atleast an amount equivalent to 5 mcg ethinyl estradiol.
 28. The kitaccording to claim 27, wherein the kit contains about 5 to about 9dosages of the Phase I composition; about 5 to about 9 dosages of thePhase II composition; and about 8 to about 12 dosages of the Phase IIIcomposition.
 29. The kit according to claim 28, wherein the kit furthercomprises about 1 to about 4 dosages of a Phase IV composition whichcontains ferrous fumarate or is a placebo.
 30. The kit according toclaim 29, wherein the progestogen in each Phase is norethindroneacetate.
 31. The kit according to claim 30, wherein the estrogen in eachPhase is ethinyl estradiol.
 32. The kit according to claim 31, whereinthe Phase II composition contains about 20 to about 40 mcg of ethinylestradiol and the Phase III composition contains about 25 to about 50mcg of ethinyl estradiol.
 33. The kit according to anyone of claims 27to 29, wherein each of the Phase I, II and III compositions contains aprogestogen in an amount equivalent to about 0.5 to about 1.5 mg ofnorethindrone acetate.
 34. The kit according to anyone of claims 30 to32, wherein each of the Phase I, II and III compositions containsnorethindrone acetate in an amount from about 0.5 to about 1.5 mg. 35.The kit according to claim 32, wherein the Phase I composition containsabout 1 mg of norethindrone acetate, the Phase II composition containsabout 1 mg of norethindrone acetate and about 30 mcg of ethinylestradiol, the Phase III composition contains about 1 mg ofnorethindrone acetate and about 35 mcg of ethinyl estradiol, and thePhase IV composition contains about 75 mg of ferrous fumarate.
 36. Thekit according to claim 35, wherein the kit contains about 7 dosages ofthe Phase I composition, about 7 dosages of the Phase II composition,about 10 dosages of the Phase III composition and about 4 dosages of thePhase IV composition.
 37. The kit according to claim 35, wherein thePhase I composition contains about 5 mcg of ethinyl estradiol.
 38. Thekit according to claim 35, wherein the Phase I composition issubstantially free of ethinyl estradiol.
 39. The kit according to claim36, wherein the Phase I composition contains about 5 mcg of ethinylestradiol.
 40. The kit according to claim 36, wherein the Phase Icomposition is substantially free of ethinyl estradiol.